Complementary and alternative medicine and musculoskeletal pain in the first year of adjuvant aromatase inhibitor treatment in early breast cancer patients.

BACKGROUND: Patients with breast cancer (BC) show strong interest in complementary and alternative medicine (CAM), particularly for adverse effects of adjuvant endocrine treatment - e.g., with letrozole. Letrozole often induces myalgia/limb pain and arthralgia, with potential noncompliance and treatment termination. This analysis investigated whether CAM before aromatase inhibitor (AI) therapy is associated with pain development and the intensity of AI-induced musculoskeletal syndrome (AIMSS) during the first year of treatment. PATIENTS AND METHODS: The multicenter phase IV PreFace study evaluated letrozole therapy in postmenopausal, hormone receptor-positive patients with early BC. Patients were asked about CAM use before, 6 months after, and 12 months after treatment started. They recorded pain every month for 1 year in a diary including questions about pain and numeric pain rating scales. Data were analyzed for patients who provided pain information for all time points. RESULTS: Of 1396 patients included, 901 (64.5%) had used CAM before AI treatment. Throughout the observation period, patients with CAM before AI treatment had higher pain values, for both myalgia/limb pain and arthralgia, than non-users. Pain increased significantly in both groups over time, with the largest increase during the first 6 months. No significant difference of pain increase was noted regarding CAM use. CONCLUSIONS: CAM use does not prevent or improve the development of AIMSS. Pain intensity was generally greater in the CAM group. Therefore, because of the risk of non-compliance and treatment discontinuation due to the development of higher pain levels, special attention must be paid to patient education and aftercare in these patients.

Activation of the aryl hydrocarbon receptor suppresses sensitization in a mouse peanut allergy model.

Food allergy is an increasing health problem in Western countries. Previously, it has been shown that the intensity of food allergic reactions can be regulated by regulatory T (T(reg)) cells. In addition, it has been shown that activation of the aryl hydrocarbon receptor (AhR) regulates T-cell responses by induction of T(reg) cells. Therefore, we hypothesized that activation of the AhR pathway can suppress development of food allergic responses through the induction of T(reg) cells. This was investigated by using a mouse model for peanut allergy. C3H/HeOuJ mice (AhR(b)(-2)) were sensitized to peanut by administering peanut extract (PE) by gavage in the presence of cholera toxin and were treated with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.6, 1.7, 5, and 15 µg/kg body weight) on days 3 and 11 orally. The functional role of CD4(+)CD25(+)Foxp3(+) T(reg) cells was investigated by depleting these cells with anti-CD25 mAb during sensitization to PE. TCDD treatment dose dependently suppressed sensitization to peanut (PE-specific IgE, IgG1, and IgG2a and PE-induced IL-5, IL-10, and IL-13, respectively). The percentage, but not the number, of CD4(+)CD25(+)Foxp3(+) T(reg) cells dose dependently increased by AhR activation in both spleen and mesenteric lymph nodes. Depletion of CD4(+)CD25(+)Foxp3(+) T(reg) cells markedly reversed the suppressive effect of TCDD on PE-specific antibody levels and PE-induced IL-5, IL-10, and IL-13 cytokine production. Present data demonstrate for the first time that activation of the AhR by TCDD suppressed the development of Th2-mediated food allergic responses. A functional shift within the CD4(+) cell population toward CD4(+)CD25(+)Foxp3(+) T(reg) cells appeared to underlie this effect. This suggests that the AhR pathway might provide potential therapeutic targets to treat food allergic diseases.

Safety of St. John's Wort extract compared to synthetic antidepressants.

The clinical efficacy of some standardized St. John's Wort extracts (SWEs) such as WS((R)) 5570, WS((R)) 5572 or LI 160 in the treatment of mild, moderate and severe major depression has been demonstrated in 38 controlled clinical trials and two recent meta-analyses. Sixteen post-marketing surveillance studies with such preparations, based on a total of 34,804 patients, recorded an incidence of adverse events (AEs) among patients between 0% and 6%. Of these studies, the four large-scale surveillance studies with a total of 14,245 patients recorded a rate of AEs ranging from 0.1% to 2.4% and a drop-out rate due to AEs of 0.1-0.9%. This is at least ten-fold lower than that recorded with synthetic antidepressants. AEs associated with SWE treatment were mild and transient in nearly all cases. As with synthetic antidepressants, pharmacokinetic interactions may occur occasionally as a result of activity changes of drug-metabolising and drug-transporting proteins, especially CYP 3A4 and P-gp. Risks to the patient are not caused by SWE but by drugs with a narrow therapeutic range. Consequently, SWE preparations should not be taken concurrently with other antidepressants, with coumarin-type anticoagulants, the immunosuppressants cyclosporine and tacrolimus, protease and reverse transcriptase inhibitors used in anti-HIV treatment or with certain antineoplastic agents. However, such cases are extremely rare and, with medical supervision, easily avoided. In conclusion, the safety of SWE must be considered more favourable than that of synthetic antidepressants.

Methadone in the management of intractable neuropathic noncancer pain.

OBJECTIVE: To evaluate the role of methadone in the management of intractable neuropathic noncancer pain. METHODS: A case series of 50 consecutive noncancer pain patients who were seen at a tertiary care centre and treated with oral methadone for a variety of intractable neuropathic pain states. RESULTS: The mean age was 52.7 years and the mean duration of follow-up was 13.9 months. Post-discectomy nerve root fibrosis, complex regional pain syndrome, peripheral neuropathy and central spinal cord pain syndromes were the most common diagnoses. Over 90% had been treated with one or more tricyclic antidepressants and anticonvulsants and a similar number had received other adjuvant analgesics. All patients had failed treatment with one or more conventional opioid analgesics (mean 2.8) at a mean maximal morphine dose of 384 mg (or equivalents) per day. Twelve patients had failed spinal cord stimulation. Nineteen patients (38%) did not tolerate initial methadone titration or thought their pain was worse on methadone. Five patients (10%) declared initial benefit but required repetitive dose escalation and eventually became non-responders. Twenty-six patients (52%) reported mild (4), moderate (15), marked (6) or complete (1) pain relief and continued on methadone at a mean maintenance dose of 159.8 mg/day for a mean duration of 21.3 months. Fourteen patients (28%) reported improved function on methadone relative to previous treatments. CONCLUSIONS: Methadone appears to have unique properties including N-methyl-D-aspartate antagonist activity that may make it especially useful in the management of intractable neuropathic pain. This observation needs to be tested in randomized, controlled trials.

[Herbal drugs: luxury or basic therapy in federal insurance practice?]. / Pflanzliche Arzneimittel: Luxus- oder Basistherapie in der kassenärztlichen Praxis?

Over the past 6 years SHI-accredited prescriptions for herbal medicinal products have decreased in Germany by around 40% (Social Health Insurance). However, this has not reduced overall drug expenditure for the statutory health insurers; in fact costs have increased more sharply than before. This development was recently explained by "Modernisation of Pharmacotherapy" which picked out 5 groups as examples. The present paper examines one of these examples, i.e. modern antidepressant therapy, and compares it with the results of recent studies and meta-analyses of herbal and synthetic preparations. Above all, the comparison for this indication revealed that the medication itself, independent of which group it belongs to, contributes merely one third of the treatment results whereas the remaining two thirds are contributed by therapists and their surroundings. Experienced physicians achieve virtually the same treatment results with suitable St. John's wort preparations as they do with modern synthetic antidepressants. Hence, medically supervised therapy with herbal medicinal products for suitable indications could avoid billions in development and treatment costs for supposedly innovative drugs. These savings would then benefit broader basic therapy.

Incidence and clinical relevance of the interactions and side effects of Hypericum preparations.

Observational studies with preparations of St. John's wort have recorded an incidence of adverse events (AE) among those treated of between 1 and 3%. This is some ten times less than with synthetic antidepressants. The most common adverse events (1 per 300000 treated cases) among the spontaneous reports in the official register concern reactions of the skin exposed to light. Investigations in volunteers have shown that the threshold dose for an increased risk of photosensitisation is about 2-4 g/day of a usual commercial extract (equivalent to approximately 5-10 mg of the hypericin that causes the phenomenon). In view of the newly observed side effects and interactions, the following additional restrictions on use appear justified: as with all preparations in this group of indications, hypericum preparations must not be taken at the same time as other antidepressants. If co-medication with coumarin-type anticoagulants is unavoidable, it must only be undertaken provided the physician closely monitors clotting parameters. Co-medication with ciclosporin and indinavir, and for the time being, other protease inhibitors used in anti-HIV treatment, is absolutely contraindicated. Without exception, all preparations of St. John's wort must only be available through pharmacies.

The psychodynamic and pharmacodynamic effects of drugs: a differentiated evaluation of the efficacy of phytotherapy.

The therapeutic usefulness of medicines is nowadays usually measured in terms of parameters devised in the artificial surroundings of a double blind clinical trial. The difference between the active drug and the placebo is accepted as being the same as the desired overall effect. Yet, when applied to whole categories of medicines, this yardstick can be misleading, as has become apparent from the discussion which has recently arisen regarding the genuine and the illusory pharmacodynamic effects of synthetic antidepressants. Differentiated analysis of a representative number of placebo-controlled studies has shown that when used for depressive conditions, the psychodynamic components contribute far more to the overall effect than do the pharmacodynamic components. In this respect, modern synthetic antidepressants are no better than Hypericum products of plant origin. Among other things, this means that for depressive states and similar indications, the safety, tolerability and acceptability of a medicine must be given much greater weight than its pharmacodynamic effects as assessed simply by testing against a placebo. The quantification of the two therapeutic components, as can be accomplished by a placebo-controlled drug trial, has revealed that the overall outcome of therapy for various important indications of this kind is attributable predominantly to the psychodynamic component. It may reasonably be assumed that the contribution made by the pharmacodynamic effects to the overall therapeutic response will amount to only about 20-50%. This raises questions regarding the clinical relevance and economic value of placebo-controlled studies. When assessing data on drug efficacy for the purpose of licensing applications, greater attention should be given to this reality.

[Incidence and clinical relevance of interactions and side-effects of hypericum preparations]. / Häufigkeit und klinische Relevanz der Interaktionen und Nebenwirkungen von Hypericum-Präparaten.

Observational studies with preparations of St. John's wort have recorded an incidence of adverse events (AE) among those treated of between 1 and 3%. This is some ten times less than with synthetic antidepressants. The most common adverse events (1 per 300,000 treated cases) among the spontaneous reports in the official register concern reactions of the skin exposed to light. Investigations in volunteers have shown that the threshold dose for an increased risk of photosensitisation is about 2-4 g/day of a usual commercial extract (equivalent to approximately 5-10 mg of the hypericin that causes the phenomenon). In view of the newly observed side effects and interactions, the following additional restrictions on use appear justified: as with all preparations in this group of indications, hypericum preparations must not be taken at the same time as other antidepressants. If co-medication with coumarin-type anticoagulants is unavoidable, it must only be undertaken provided clotting parameters are closely monitored by the physician. Co-medication with cyclosporin and indinavir, and for the time being, other protease inhibitors used in anti-HIV treatment, is absolutely contraindicated. Without exception, all preparations of St. John's wort must only be available through pharmacies.

[St. Johns wort extract as plant antidepressant]. / Johanniskraut-Extrakt als pflanzliches Antidepressivum.

In 1998 a standardized hypericum extract has been approved in Austria and Germany for treatment of mild and moderate depression. The efficacy has been already recognized since 1984 from the German Health Authorities based on traditional knowledge. However, this has been substantiated in the subsequent years in controlled clinical trials. Twenty of these studies including a total of 1787 patients have been filed, among them ten older studies in which hypericum was extracted with ethanol compared to newer studies in which the extract was methanol (LI 160). In the past ten years several controlled clinical trials have been conducted compared with placebo as well as synthetic antidepressants. These studies have shown that the effective dosage is within a range of 600-900 mg extract. The side effects are substantially fewer than with synthetic antidepressants and range within 3%. The most important risk is photosensitization, which is however without clinical relevance in the recommended dosages. Recent pharmacological studies revealed that hypericum extracts have a similar mechanism of action like the selective serotonin reuptake inhibitors (SSRI), however, very likely to a smaller extent.

[High dose St. John's wort extract as a phytogenic antidepressant]. / Hochdosierter Johanniskraut-Extrakt als pflanzliches Antidepressivum.

In 1998 a special standardized high-dose hypericum extract has been approved in Austria and Germany for treatment of mild and moderate depression. The efficacy has been already recognized since 1984 from the German Health Authorities based on traditional knowledge. However, this has been substantiated in the subsequent years in controlled clinical trials. 20 of these studies including a total of 1,787 patients have been filed, among them 10 older studies in which hypericum was extracted with ethanol compared to newer studies in which the extract was methanol (LI 160). In the past 10 years several controlled clinical trials have been conducted compared with placebo as well as synthetic antidepressants. These studies have shown that the effective dosage is within a range of 600 to 900 mg extract. The side effects are substantially fewer than with synthetic antidepressants and range within 3%. The most important risk is photosensitization, which is however without clinical relevance in the recommended dosages. Recent pharmacological studies revealed that hypericum extracts have a similar mechanism of action like the selective serotonin reuptake inhibitors (SSRI), however, very likely to a smaller extent.

Clinical trials with Phyto-Psychopharmacological agents.

Phyto-psychopharmacological agents are extracts of plants with stimulating or calming effects on the central nervous system. Phyto-psycho-pharmacological agents are among the most commonly prescribed herbal medicines in Germany. The efficacy and harmlessness of some of the preparations have been established by high quality clinical trials. Between 1975 and 1992, a total of 34 clinical studies involving some 2326 patients were published on the effects of Ginkgo special extract EGb 761 and LI 1370; to date, 28 clinical trials in 2120 patients have been under-taken with alcoholic extracts of St. John's Wort. The therapeutic efficacy of kava and valerian extracts has been investigated in six and four controlled studies, respectively. In general, a high placebo effect is likely, which is why it is essential to include control groups in these studies. A considerable advantage over synthetic psychopharmacological agents is the low incidence of side effects, which in safety assessment studies is below 3%. The sharp increase in quality standards for clinical trials has meant that only a few preparations have undergone large scale testing programs in accordance with international guidelines. For other phyto-psychopharmacological agents, there is the danger that no further clinical trials will be undertaken due to the excessively high standards now demanded.

Clinical investigation of the antidepressant effectiveness of hypericum.

To date, 25 controlled therapy studies have investigated the antidepressive effectiveness of hypericum extracts. A total of 1592 treatment cases have been included. The dosage was typically 300 to 900 mg total extract daily; the therapy duration was 2 to 6 weeks. Fifteen studies were performed comparing hypericum extracts with placebo, 10 studies as comparative studies. This paper presents an overview of their results.

[Resorption of hydrocyanic acid from linseed]. / Resorption von Blausäure aus Leinsamen.

Resorption of hydrocyanic acid after ingestion of linseed was investigated in 20 healthy volunteers and 5 patients. The persons investigated took a single dose of 30 g or of 100 g of linseed or they received throughout several weeks 15 g. t.i.d. One volunteer also took for purposes of comparison bitter almonds or potassium cyanide. Before, during and after the periods of ingestion plasma levels of hydrocyanic acid and of thiocyanate were normal. During long-term trials urinary excretion of thiocyanate was monitored regularly. Intake of linseed even in extremely high dosages never caused significant rises of plasma thiocyanate levels; this, however, was the case after intake of bitter almonds or potassium cyanide. Thus, it can be excluded, that intoxication by hydrocyanic acid can be caused by linseed. Long-term intake of linseed however, raised plasma levels of thiocyanate significantly; at the same time urinary excretion of thiocyanate increased.

Physiological data including evaluation of immuno-response in relation to anabolic effects on veal calves.

In a series of experiments with a total of 1480 veal calves, different aspects of treating calves with anabolic steroids were examined. The anabolics used were 17beta-estradiol (E), trenbolone acetate (T), progesterone (P), testosterone (Te), C+T, E+P, E+Te and zeranole (Z). The N-retention was estimated by examining the urea: creatinine ratio in single urine specimens during the course of two feeding trials. Increased gain due to the treatment with E (20 mg implanted/calf) + P (200 mg) and Te (200 mg), respectively, E + T (140 mg) or Z (36 mg) was during the whole experimental period. The extra gain, due to anabolics seems to contain even more protein. This conclusion may be supported by the crude protein content of meat samples. The antibody production of a total of 311 male and female calves was investigated after the application of the following steroids: E (20 mg), T (200 mg), T (200 mg), E + T, P (200 mg), Te (200 mg), E + P, E + Te, and Z. Eleven days after the implantation of the steroids the animals were immunized with alumprecipitated human serumalbumin. Antibody-titres were determined by the Antigen-Binding-Capacity Test on day 14 following immunization. In nearly all groups the antibody-titres of female calves exceeded those of male calves on the average by 75%. The immune response of all experimental groups did not differ significantly from that of the corresponding control groups. However, the results indicate that both E + T and its single components E and T exert an immunodepressive effect in male calves. While the humoral antibody formation in the calf appears not to be influenced by anabolic steroids, it cannot be decided presently whether these substances effect cell-mediated immune reactions and/or unspecific mechanisms of resistance. When estradiol (20, 200, and 500 mg) and trenbolone acetate (140, 1400, 3500 mg) alone and in combination were implanted in female calves, blood glucose, GOT, GPT, alkaline phosphatase, LDH, cholesterine and bilirubine; Hb, PVC, quick value; urine density and pH were not affected by treatment. Some criteria of the mineral metabolism (Ca- and P-levels in serum and bone) was not altered by treatment. Trenbolone (1 400 and 3 500 mg), especially with estradiol, caused a decrease of the serum Mg-level and of the Mg-deposition in the bone. It is discussed that Trenbolone affects the dig-metabolism of calves. Some morphological findings are worth mentioning. The weight of uterus was not affected by the different doses of E or T, but a combination E + T led to a surprising weight increase. The proliferation of uterine glandular cells was responsible for the increased uterine size. The lumen of uterus was partially filled with a watery liquid. The reduction of the ovarian weight was accompanied by a diminution of follicular size for all treated calves, most evident for E (200, 500 mg) + T (1400, 3500 mg). A decrease in the number of follicles was also found for these two groups. T (3500 mg) caused an abnormal size of the clitoris and led to a reduction of the size of thymus.